Simvastatin of formula I is known to be active inhibitors of HMG-CoA reductase. The therapeutic uses of simvastatin and related compounds were disclosed in U.S. Pat. No. 4,444,784.

Various processes for preparing simvastatin were disclosed in the prior art. Processes described in the prior art for preparation of simvastatin can be summarized as under: 1) according to U.S. Pat. No. 4,444,784, lovastatin is hydrolyzed with lithium hydroxide to give lovastatin triol, lactonized to give a diol lactone, silylated 3-OH group, acylated and finally desilylated; 2) according to U.S. Pat. No. 4,582,915, lovastatin is hydrolyzed to give lovastatin potassium salt, directly C-methylated at alpha position of 2-methyl butyryl side chain and lactonized; 3) according to U.S. Pat. No. 4,820,850, lovastatin is reacted with monoalkylamine to produce lovastatin monoalkylamide, hydroxy groups are protected with t-butyidimethylsilyl groups, C-methylated at alpha position of 2-methyl butyryl side chain, deprotected, hydrolyzed the amide linkage and lactonized; 4) according to U.S. Pat. No. 5,763,646, lovastatin is reacted with monoalkylamine or monocycloalkylamine to produce lovastatin monoalkyl or cycloalkylamide, C-methylated at alpha position of 2-methyl butyryl side chain, hydrolyzed the amide linkage and lactonized; 5) according to U.S. Pat. No. 6,331,641 B1, lovastatin is hydrolyzed with a base to give lovastatin triol, lactonized to give a diol lactone, protected the hydroxy groups, acylated, deprotected and lactonized; 6) according to U.S. Pat. No. 6,603,022 B1, lovastatin is reacted with secondary amine to form a lovastatin amide, C-methylated at alpha position of 2-methyl butyryl side chain, hydrolyzed the amide linkage and lactonized; and 7) according to U.S. Pat. No. 5,393,893, hydroxyl groups of lovastatin alkylamide, cycloalkylamide or aralkyl amide are protected with phenyl boronic acid, C-methylated at alpha position of 2-methyl butyryl side chain, deprotected, hydrolyzed the amide linkage and lactonized.
The above processes suffer from one or other of the following defects. Selective silylation of triol intermediates is not satisfactory leading to the low overall yield and the contamination of the final product with unacylated impurity. Incomplete C-methylation of N-alkyl, cycloalkyl or aralkyl of lovastatinamide, which leads to contamination of simvastatin with lovastatin, thereby requiring additional purification steps.
The present invention provides a novel process for preparing simvastatin in high purity using novel intermediates. The novel process overcomes the aforesaid defects and is amicable for commercial scale production.